Method of treating attention deficit disorders with d-threo methylphenidate

ABSTRACT

Methods for treating Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, AIDS Dementia Complex and cognitive decline in HIV-AIDS while minimizing drug hypersensitivity, toxicity, side effects, euphoric effect, and drug abuse potential by administration of d-threo-methylphenidate or pharmaceutically acceptable salts thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 13/093,917, filed Apr.26, 2011, which is a continuation of U.S. application Ser. No.12/580,800, filed Oct. 16, 2009, which is a continuation of U.S.application Ser. No. 11/244,924 (now abandoned), filed Oct. 6, 2005,which is a continuation of U.S. application Ser. No. 10/961,122 (nowabandoned), filed Oct. 8, 2004; which is a continuation of U.S.application Ser. No. 10/395,444, filed Mar. 24, 2003 (now abandoned);which is a continuation of U.S. application Ser. No. 09/864,617, filedMay 24, 2001 (now U.S. Pat. No. 6,602,887; which is a divisional of U.S.application Ser. No. 09/337,310, filed Jun. 21, 1999 (now U.S. Pat. No.6,255,325); which is a divisional of U.S. application Ser. No.08/937,684, filed Sep. 29, 1997 (now U.S. Pat. No. 5,922,736); which isa continuation-in-part of U.S. application Ser. No. 08/827,230, filedApr. 2, 1997 (now U.S. Pat. No. 5,908,850), which is acontinuation-in-part of U.S. application Ser. No. 08/647,642, filed May15, 1996, (now abandoned), which is a continuation-in-part of U.S.application Ser. No. 08/583,317, filed Jan. 5, 1996, (now U.S. Pat. No.5,733,756), which is a continuation of U.S. application Ser. No.08/567,131, filed Dec. 4, 1995 (now abandoned); all of which areincorporated herein.

FIELD OF THE INVENTION

The present invention relates to methods of treating certain CentralNervous System disorders such as Attention Deficit Disorder (ADD),Attention Deficit Hyperactivity Disorder (ADHD), HIV/AIDS cognitivedecline, and AIDS Dementia Complex with decreased side effects, reducedeuphoric effect, and reduced drug abuse potential.

BACKGROUND OF THE INVENTION

Attention Deficit Disorder (ADD) is the most commonly diagnosed illnessin children. Patrick et al., J. Pharmacol. & Exp. Therap., 241:152-158(1987). Symptoms of ADD include distractibility and impulsivity. Arelated disorder, termed Attention Deficit Hyperactivity Disorder(ADHD), is further characterized by increased symptoms of hyperactivityin patients. Racemic methylphenidate (e.g., Ritalin®) is a mild CentralNervous System stimulant with pharmacological activity qualitativelysimilar to amphetamines, and has been the drug of choice for symptomatictreatment of ADD in children. Greenhill, L., Child & Adol. Psych. Clin.N.A., Vol. 4, Number 1:123-165 (1995). Current administration of racemicmethylphenidate, however, results in notable side effects such asanorexia, weight loss, insomnia, dizziness and dysphoria. Additionally,racemic methylphenidate which is a Schedule II controlled substance,produces a euphoric effect when administered intravenously or throughinhalation, and thus carries a high potential for substance abuse inpatients.

At least 70% of HIV-infected individuals who have developed AcquiredImmunodeficiency Syndrome (AIDS) eventually manifest cognitive defects,and many display signs and symptoms of dementia. See Navia et al.,Annals of Neurology, 19:517-524 (1986). Complaints of forgetfulness,loss of concentration, fatigue, depression, loss of attentiveness, moodswings, personality change, and thought disturbance are common inpatients with Human Immunodeficiency Virus (HIV) disease. Douzenis etal., Proc. 7th Int'l. Conf. AIDS, 1, MB, 2135:215 (1991); Holmes et al.,J. Clin. Psychiatry, 50:5-8 (1989). Racemic methylphenidate has beenused to treat cognitive decline in AIDS/ARC patients. Brown, G., Intl.J. Psych. Med. 25(1): 21-37 (1995). As described above, racemicmethylphenidate which is a Schedule II controlled substance, produces aeuphoric effect when administered intravenously or through inhalation,and thus carries a high potential for drug abuse in AIDS patients.

Glutathione is an important antioxidative agent that protects the bodyagainst electrophilic reactive compounds and intracellular oxidants. Ithas been postulated that HIV-AIDS patients suffer from drughypersensitivity due to drug overload and an acquired glutathionedeficiency. See Uetrecht et al., Pharmacol. Res., 6:265-273 (1989).Patients with HIV infection have demonstrated a reduced concentration ofglutathione in plasma, cells and broncho-alveolar lavage fluid. Staal etal., Lancet, 339:909-912 (1992). Clinical data suggests thatHIV-seropositive individuals display adverse reactions to thesimultaneous administration of several otherwise therapeutic drugs.Rieder et al., Ann. Intern. Med., 110:286-289 (1989). It is thereforedesirable to provide for the administration of methylphenidate inreduced dosages among patients with drug hypersensitivity due to HIVinfection.

Methylphenidate possesses two centers of chirality and thus can exist asfour separate optical isomers. The four isomers of methylphenidate areas follows:

Diastereomers are known in the art to possess differing physicalproperties, such as melting point and boiling point. For example, whilethe threo-racemate of methylphenidate produces the desired CentralNervous System action, the erythro-racemate contributes to hypertensiveside effects and exhibits lethality in rats.

Additional studies in animals, children and adults have demonstratedpharmacological activity in the d-threo isomer of methylphenidate(2R:2′R). See Patrick et al., J. Pharmacol. & Exp. Therap., 241:152-158(1987). Although the role of the 1-isomer in toxicity or adverse sideeffects has not been thoroughly examined, the potential for isomerballast in methylphenidate is of concern for many patient groups,particularly those drug hypersensitive patients as described above.

Although 1-threo-methylphenidate is rapidly and stereo-selectivelymetabolized upon oral administration, intravenous administration orinhalation results in high 1-threo-methylphenidate serum levels.Srinivas et al., Pharmacol. Res., 10:14-21 (1993). Intravenousadministration and inhalation are the methods of choice by drug abusersof current methylphenidate formulations. The present inventionpostulates that the euphoric effect produced by current formulations ofmethylphenidate is due to the action of 1-threo-methylphenidate.

Accordingly, it has been discovered that the use of the d-threo isomer(2R:2′R) of methylphenidate, substantially free of the 1-threo isomerproduces a methylphenidate medication which retains high activity levelsand simultaneously possesses reduced euphoric effect and reducedpotential for abuse among patients.

U.S. Pat. No. 2,507,631, to Hartmann et al. describes methylphenidateand processes for making the same.

U.S. Pat. No. 2,957,880, to Rometsch et al. describes the conversion of.alpha.-aryl-.alpha.-piperidyl-(2)-acetic acids and derivatives thereof(including methylphenidate) into their respective racemates.

Holmes et al., J. Clin. Psychiatry, 50:5-8 (1989) reported on the use ofracemic methylphenidate (Ritaline®) and dextroamphetamines in thetreatment of cognitive impairment in AIDS patients.

Srinivas et al., J. Pharmacol. & Exp. Therap., 241:300-306 (1987)described use of racemic dl-threo-methylphenidate (Ritalin®) in thetreatment of ADD in children. This study noted a 5-fold increase inplasma levels of d-threo-methylphenidate in children treated withracemic methylphenidate, but was otherwise inconclusive with regard tothe efficacy of a single methylphenidate isomer at therapeuticallysignificant doses.

Srinivas et al., Clin. Pharmacol. Ther., 52:561-568 (1992) studied theadministration of dl-threo, d-threo and 1-threo-methylphenidate tochildren suffering from ADHD. While Srinivas et al. reported thepharmacodynamic activity of dl-threo-methylphenidate resides in thed-threo isomer, this study investigated neither the adverse side effectsof the 1-threo isomer, nor the euphoric effects of the single isomers orracemate. Single isomer dosages below ½ of the racemate dosage were notstudied.

Patrick et al., J. Pharmacol. & Exp. Therap., 241:152-158 (1986)examined the pharmacology of the enantiomers of threo-methylphenidate,and assessed the relative contribution of each isomer to central andperipheral actions of Ritalin®.

Brown, G., Intl. J. Psych. Med., 25(1):21-37 (1995) reported the use ofracemic methylphenidate for the treatment of AIDS cognitive decline.

Patrick et al., Psychopharmacology: The Third Generation of Progress,Raven Press, N.Y. (1987) examined the pharmacokinetics and actions ofmethylphenidate in the treatment of Attention Deficit HyperactivityDisorder (ADHD). Patrick noted the d-threo isomer possesses higheractivity than the 1-threo isomer, and that d-threo methylphenidate maybe responsible for the therapeutic activity in the racemic drug.

Aoyama et al., Clin. Pharmacol. Ther., 55:270-276 (1994) reported on theuse of (+)-threo-methylphenidate in the treatment of hypersomnia Aoyamaet al. describe a correlation between sleep latency in patients andplasma concentration or (+)-threo-methylphenidate.

SUMMARY OF THE INVENTION

The present invention is based on the discovery thatd-threo-methylphenidate (2R:2′R) possesses enhanced therapeutic activitywith reduced side effects, and 1-threo-methylphenidate producesundesirable side effects, euphoria and drug abuse potential in patientssuffering from Attention Deficit Disorder, Attention DeficitHyperactivity Disorder, AIDS cognitive decline, and AIDS DementiaComplex.

The present invention thus relates to methods of treating AttentionDeficit Disorder and Attention Deficit Hyperactivity Disorder inchildren and adults while providing for reduced side effects, reducedeuphoric effect and reduced potential for abuse potential throughadministration of d-threo-methylphenidate (2R:2′R) of the formula:

or a pharmaceutically acceptable salt thereof, substantially free of the1-threo isomer.

The invention further relates to methods of treating AIDS-relateddementia and related cognitive disorders while providing for reducedside effects, reduced euphoric effect, and reduced abuse potentialthrough administration of d-threo-methylphenidate (2R:2′R) of theformula:

or a pharmaceutically acceptable salt thereof, substantially free of the1-threo isomer.

Prescription of methylphenidate to treat AIDS cognitive decline and AIDSDementia Complex associated with HIV infection is becoming increasinglypopular. However, high doses in excess of 40 mg/day are not welltolerated by a substantial number of HIV-infected patients when treatedover weeks or months. Brown, G., Int'l J. Psychiatry. Med., 25:21-37(1995). The d-threo isomer use of the present invention thus enables alowered dosing therapy resulting in improved efficacy for diseasedpatients and particularly HIV-infected patients.

Moreover, administration of the d-threo isomer to patients will resultin decreased side effects, reduced euphoric effect, and substantiallyreduce the potential for abuse of the product.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Racemic methylphenidate and its individual isomers are known. See U.S.Pat. Nos. 2,507,631 and 2,957,880. They can be prepared by conventionaltechniques, and can be obtained from a variety of commercial sources.

The d-threo isomer of the present invention can be administered orally,rectally, parenterally, or transdermally, alone or in combination withother psychostimulants, antidepressants, and the like to a patient inneed of treatment. Oral dosage forms include tablets, capsules, dragees,and similar shaped compressed pharmaceutical forms. Isotonic salinesolutions containing 20-100 milligrams/milliliter can be used forparenteral administration which includes intramuscular, intrathecal,intravenous and intra-arterial routes of administration. Rectaladministration can be effected through the use of suppositoriesformulated from conventional carriers such as cocoa butter. Transdermaladministration can be effected through the use of transdermal patchdelivery systems and the like. The preferred routes of administrationare oral and parenteral.

The dosage employed must be carefully titrated to the patient,considering age, weight, severity of the condition, andclinical-profile. Typically, the amount of d-threo-methylphenidateadministered will be in the range of 5-50 mg/day, but the actualdecision as to dosage must be made by the attending physician.

The present invention provides enhanced relief for patients sufferingfrom Attention Deficit Disorder and Attention Deficit HyperactivityDisorder while providing for reduced side effects, reduced euphoriceffect, and reduced abuse potential through administration ofd-threo-methylphenidate substantially free of the 1-threo isomer.

The invention further provides for treatment of AIDS-related dementiaand related cognitive disorders with d-threo-methylphenidatesubstantially free of the 1-threo isomer while providing for reducedside effects, reduced euphoric effect, and reduced abuse potential.

The term, “substantially free of the 1-threo-isomer” means that thecomposition contains at least 90% by weight of d-threo-methylphenidate,and 10% by weight of 1-threo-methylphenidate. In the most preferredembodiment, the term “substantially free of the 1-threo isomer” meansthat the composition contains at least 99% by weight ofd-threo-methylphenidate and 1% or less of 1-threo-methylphenidate.

The following examples will serve to further typify the nature of theinvention, but should not be construed as a limitation on the scopethereof, which is defined solely by the appended claims.

Example 1

Tablets for chewing, each containing 5 milligrams ofd-threo-methylphenidate, can be prepared in the following manner:

Composition (for 1000 tablets) d-threo-methylphenidate 5.00 gramsmannitol 15.33 grams  lactose 10.00 grams  talc 1.40 grams glycine 0.83grams stearic acid 0.66 grams saccharin 0.10 grams 5% gelatin solutionq.s.

All the solid ingredients are first forced through a sieve of 0.25 mmmesh width. The mannitol and the lactose are mixed, granulated with theaddition of gelatin solution, forced through a sieve of 2 mm mesh width,dried at 50° C. and again forced through a sieve of 1.7 mm mesh width.The d-threo-methylphenidate, the glycine and the saccharin are carefullymixed, the mannitol, the lactose granulate, the stearic acid and thetalc are added and the whole is mixed thoroughly and compressed to formtablets of approximately 10 mm diameter which are concave on both sidesand have a breaking groove on the upper side.

Example 2

Tablets, each containing 10 milligrams of d-threo-methylphenidate, canbe prepared in the following manner:

Composition (for 1000 tablets) d-threo-methylphenidate 10.0 gramslactose 328.5 grams corn starch 17.5 grams polyethylene glycol 6000 5.0grams talc 25.0 grams magnesium stearate 4.0 grams demineralized waterq.s.

The solid ingredients are first forced through a sieve of 0.6 mm meshwidth. Then the d-threo-methylphenidate, lactose, talc, magnesiumstearate and half of the starch are intimately mixed. The other half ofthe starch is suspended in 65 milliliters of water and this suspensionis added to a boiling solution of the polyethylene glycol in 260milliliters of water. The resulting paste is added to the pulverulentsubstances, and the whole is mixed and granulated, if necessary with theaddition of water. The granulate is dried overnight at 35° C., forcedthrough a sieve of 1.2 mm mesh width and compressed to form tablets ofapproximately 10 mm diameter which are concave on both sides and have abreaking notch on the upper side.

Example 3

Gelatin dry-filled capsules, each containing 20 milligrams ofd-threo-methylphenidate, can be prepared in the following manner

Composition (for 1000 capsules) d-threo-methylphenidate 20.0 grams microcrystalline cellulose 6.0 grams sodium lauryl sulfate 0.4 gramsmagnesium stearate 1.6 grams

Example 3

The sodium lauryl sulfate is sieved into the d-threo-methylphenidatethrough a sieve of 0.2 mm mesh width and the two components areintimately mixed for 10 minutes. The microcrystalline cellulose is thenadded through a sieve of 0.9 mm mesh width and the whole is againintimately mixed for 10 minutes. Finally, the magnesium stearate isadded through a sieve of 0.8 mm width and, after mixing for a further 3minutes, the mixture is introduced in portions of 28 milligrams eachinto size 0 (elongated) gelatin dry-fill capsules.

Example 4

A 0.2% injection or infusion solution can be prepared, for example, inthe following manner:

d-threo-methylphenidate 5.0 grams sodium chloride 22.5 grams phosphatebuffer pH 7.4 300.0 grams demineralized water to 2500 mL.

The d-threo-methylphenidate is dissolved in 1000 milliliters of waterand filtered through a microfilter or slurried in 1000 mL of H₂O. Thebuffer solution is added and the whole is made up to 2500 milliliterswith water. To prepare dosage unit forms, portions of 1.0 or 2.5milliliters each are introduced into glass ampoules (each containingrespectively 2.0 or 5.0 milligrams of d-threo-methylphenidate).

What is claimed:
 1. A method of treating Attention Deficit HyperactivityDisorder comprising administrating on a daily basis to a human havingAttention Deficit Hyperactivity Disorder, 5 to 50 mg of D-threomethylphenidate, or a pharmaceutically acceptable salt thereof,substantially free of L-threo methylphenidate, wherein the D-threomethylphenidate, or pharmaceutically acceptable salt, is mixed with apharmaceutically acceptable carrier, diluent, or excipient.
 2. Themethod according to claim 1 wherein the amount of D-threomethylphenidate administered is 5 mg per day.
 3. The method according toclaim 1 wherein the amount of said D-threo methylphenidate, or apharmaceutically equivalent salt thereof, is greater than 90% of thetotal amount of methylphenidate.
 4. The method according to claim 4wherein the amount of said D-threo methylphenidate, or apharmaceutically equivalent salt thereof, is greater than 99% of thetotal amount of methylphenidate.
 5. The method according to claim 1wherein the amount of D-threo methylphenidate enhances therapeuticactivity compared to racemic methylphenidate.
 6. The method according toclaim 1 wherein the administration is one to four times per day.
 7. Themethod according to claim 1 wherein the amount of D-threomethylphenidate administered is 20 mg per day.
 8. The method accordingto claim 1 wherein the amount of D-threo methylphenidate administered is50 mg per day.